Low body mass index as a predictor of sputum culture conversion and treatment outcomes among patients receiving treatment for multidrug-resistant tuberculosis in Lesotho

ABSTRACT Background A low body mass index (BMI) at the start of treatment for rifampicin- or multidrug-resistant tuberculosis (MDR/RR-TB) is associated with poor treatment outcomes and may contribute to delayed sputum culture conversion, thereby prolonging the period of potential transmission to others. Whether the relative importance of low BMI in predicting treatment outcomes differs by HIV status is unclear. Objectives We evaluated the association between low BMI and two dependent variables, sputum culture conversion and end-of-treatment outcome, among patients receiving treatment for MDR/RR-TB in Lesotho, a setting with a high prevalence of HIV infection. Methods Secondary data from a prospective cohort of patients initiating a longer (18–20 months) treatment containing bedaquiline and/or delamanid under routine programmatic conditions in Lesotho were analysed. Risk ratios and differences were adjusted for potential confounders using multivariable logistic regression, and estimates were stratified by HIV status. Results Of 264 patients, 105 and 250 were eligible for culture conversion and end-of-treatment analyses, respectively. Seventy-one per cent of patients (74/105) experienced culture conversion within six months, while 74% (184/250) experienced a favourable end-of-treatment outcome. Low BMI was associated with a lower frequency of culture conversion at six months among those who were not living with HIV (relative risk [RR]: 0.50 [95% CI: 0.21, 0.79]); this association was attenuated among those living with HIV (RR: 0.88 [95% CI: 0.68, 1.23]). A low BMI was moderately associated with a lower frequency of treatment success (RR = 0.89 [95% CI: 0.77, 1.03]), regardless of HIV status. Conclusions Low BMI was common and associated with the frequency of six-month culture conversion and end-of-treatment outcomes. The association with culture conversion was more pronounced among those not living with HIV. Addressing the myriad factors that drive low BMI in this setting could hasten culture conversion and improve end-of-treatment outcomes. This will require a multipronged approach focused on alleviating food insecurity and enabling prompt diagnosis and treatment of HIV and TB.


Background
Despite the recent improvements in the treatment of multidrug-or rifampicin-resistant and resistant tuberculosis (MDR/RR-TB), not all patients experience treatment success [1,2].Even among patients receiving all-oral and/or shortened regimens, those living with HIV or advanced TB experience a higher risk of unfavourable treatment outcomes.Low body mass index (BMI) indicates advanced disease and may therefore correlate with unsuccessful treatment [3].Low BMI is also a proxy for malnutrition, including micronutrient and protein energy deficiencies, which may impact immune system functioning and, thereby, the response to treatment [4].Because malnutrition and advanced TB may occur simultaneously or singularly, the underlying cause of the low body weight may be challenging to disentangle.Regardless of the mechanism, low BMI may serve as a marker of risk or vulnerability, identifying patients needing additional care and support.
Sputum culture conversion is a marker of treatment response; delayed or no culture conversion identifies patients at high risk for an unfavourable end-of-treatment outcome [5,6].Studies from diverse settings, including two meta-analyses, have suggested that low BMI is an important prognostic factor for delayed culture conversion and poor end-oftreatment outcomes among patients undergoing treatment for MDR/RR-TB [3,[7][8][9][10][11][12][13].While some of these studies were conducted in settings with a high HIV prevalence [10,12], whether the relative importance of low BMI differs according to HIV status with regard to these outcomes remains unclear.
Lesotho is a small, landlocked country surrounded by the Republic of South Africa.The country's population is estimated at 2.2 million, with 57% living on less than one dollar a day and about 80% living in rural areas [14].TB incidence is 650 per 100,000 population, and the estimated proportion of cases that are MDR/RR-TB is 11.8% across new and previously treated cases [15].In Lesotho, the tuberculosis epidemic is fuelled by HIV (one in five adults aged 15 to 49 lives with HIV) [16].It cooccurs alongside frequent malnutrition and food insecurity arising from El Niño-induced drought.Over 57% of the population lives below the poverty line [14].
Given the synergistic epidemics of tuberculosis, HIV, food insecurity, and poverty in Lesotho, low BMI may constitute a particularly important warning sign for patients who present to care for MDR/RR-TB.Among patients treated for MDR/RR-TB with a longer regimen containing bedaquiline and/or delamanid, we examined whether a low BMI predicted culture conversion within six months of treatment or end-of-treatment success and whether these relationships were modified by HIV status.

Data resource, target population, and study sites
This secondary analysis relied on data from the prospective endTB observational cohort (NCT03259269) of patients initiating longer (18-20 month) treatment for MDR/RR-TB with a regimen containing bedaquiline and/or delamanid under routine programmatic conditions.Data from standardised forms were entered into an electronic medical record.The current analysis was restricted to patients from Lesotho who had documented MDR/RR-TB and consented to participate in the observational cohort.For analyses of culture conversion, we additionally required a positive baseline culture taken before the initiation of treatment [17,18].For the end-of-treatment (EOT) outcome analyses, patients were excluded if their EOT outcome was not evaluated (i.e. in the case of transfer out of the country).All patients in Lesotho received a monthly food package including 50 kg of maize meal, 20 kg of sorghum, 2 kg of beans, 2 kg of peas, 1 g of sugar, 5 kg of vegetable oil, and 1 g of powdered milk.This support was intended for one person and provided to enable and encourage treatment adherence and improve patients' nutritional status.

Dependent variables and definitions
Sputum culture conversion within the first six months of treatment was defined as two consecutive negative cultures collected at least 15 days apart, one before 180 days of treatment and one before 210 days of treatment [19][20][21].The second outcome was favourable EOT outcomes.In accordance with WHO guidelines, using an algorithm, we calculated the EOT outcomes based on the available culture results at the end of treatment [22].

Independent variables and definitions
The primary independent variable was BMI, which was classified into underweight (<18.5),normal weight (18.5 to 24.9), and overweight (≥25).We considered potential confounding by demographic characteristics (i.e.age and sex), substance use (i.e.alcohol use, tobacco use, injection drug use, and non-injection drug use), comorbidities (i.e.anaemia, HIV infection, diabetes mellitus or glucose intolerance, hepatitis B virus, hepatitis C virus), and TB-related characteristics (i.e.bilateral disease, cavitary disease, fibrosis, sputum culture, sputum smear, and baseline resistance profile).
Statistical analysis included descriptive statistics, bivariable analyses, and multivariable logistic regression.From the list of potential confounders identified a priori, we identified those associated with BMI and the outcomes of interest in these data and adjusted for these potential confounders.Besides the list of potential confounders, we adjusted for resistance profile at baseline and numbers of likely effective Group A drugs in the multivariable analyses.We created an interaction term between BMI and HIV status to examine whether the impact of BMI on treatment outcome differed by HIV status.The missing indicator method was used to handle missing data.In the case of model nonconvergence, we used bootstrapping with 500 random samples to calculate the risk ratio (RR), risk difference (RD), and 95% confidence intervals (CI) based on the predicted probabilities.
We conducted a secondary analysis to differentiate between underweight and severely underweight.For the analysis of culture conversion, we conducted a sensitivity analysis, which consisted of a time-toevent analysis in which we censored patients who died or became lost to follow-up before the six months of treatment.Analyses were conducted using SAS software version 9.4 (SAS Institute, Inc., Cary, NC), and the forest plot was created using the 'forestplot' package in R version 4.1.0(The R Foundation).

Research ethics
The study protocol for the endTB observational cohort was approved by the ethics review committees for the three consortium partners (i.e.Partners In Health, Medecins Sans Frontieres, and Interactive Research and Development) and in each country where the study was conducted.In Lesotho

Overview
Of the 2,789 patients enrolled in the endTB observational cohort, 264 (9%) were from Lesotho.A total of 105 and 250 patients were eligible for culture conversion analyses and end-of-treatment analyses, respectively.Seventy-one per cent of patients (74/ 105) experienced culture conversion within six months, while 74% (184/250) shared a favourable EOT outcome.Across both analytic groups, patients tended to be male and married.More than half were underweight, and a majority were living with HIV (Table 1).
In the secondary analyses, which differentiated between underweight and severely underweight, the results were consistent and did not affect the interpretation (Table A2 in   Sensitivity analyses, in which patients who died or were lost to follow-up before six months of the treatment were censored, yielded similar results.Patients who were underweight experienced a lower rate of culture conversion overall (HR: 0.44 [95% CI: 0.26, 0.78]) (Table A3 in Appendix); however, this impact tended to be stronger among patients who were HIVnegative (HR: 0.20 [95% CI: 0.07, 0.56]) as compared to those living with HIV (HR: 0.60 [95% CI: 0.31, 1.14]).

Discussion
Low BMI was common in this cohort of patients treated for MDR/RR-TB in Lesotho, most of whom also lived with HIV.Low BMI was strongly associated with a lower frequency of culture conversion at six months and moderately associated with a lower frequency of treatment success.This is similar to a study by Park et al., where low BMI was an independent risk factor for failure to achieve sputum culture conversion within three months among MDR/RR-TB patients [2,8,23].While the impact of low BMI on favourable EOT outcomes appeared to be similar among those who were and were not living with HIV, low BMI seemed to be a more important predictor of culture conversion among patients who were not living with HIV than those living with HIV.
The high prevalence of low BMI in this population suggests that targeted interventions that effectively prevent and/or mitigate this condition could impact culture conversion and treatment success.The development of such interventions requires understanding the factors driving low BMI in this setting, which are likely multifactorial.These include food insufficiency and advanced HIV and/or TB disease, all common among patients treated for MDR/RR-TB in Lesotho.A large part of the Basotho population experiences chronic food insecurity and/or nutrient deficiency, especially residents of rural areas where subsistence farming is common despite unfavourable agricultural conditions [24,25].Advanced HIV infection and delayed TB diagnosis or treatment may also be important contributors.In Lesotho, migration in pursuit of economic opportunities is common and may interfere with consistent antiretroviral treatment in the absence of differentiated programmes to ensure mechanisms for treatment retention [26,27].Traditional beliefs may contribute to tuberculosis treatment delays in Lesotho as some patients prefer to seek healthcare from traditional healers first and only present at the hospital when their clinical conditions have significantly deteriorated [28].Traditional healers have been successfully engaged to promote HIV care in Lesotho and could likewise be engaged to facilitate prompt care for tuberculosis [29].Health system challenges and centralised services may also contribute to delayed linkage to care and treatment initiation.Based on Lesotho's national drug-resistant TB guidelines, all bacteriologically confirmed drug-resistant TB patients should be referred to a specialised hospital for treatment initiation [30,31].Centralised approaches may lead to delays along the care cascade, resulting in morbidity, mortality, and ongoing TB transmission [32,33].An approach where care and treatment are decentralised to the district hospitals where patients are initiated on treatment once diagnosed may be a solution to delayed treatment initiation among MDR/RR-TB patients in the country.As a result, the country is currently implementing a decentralisation strategy for the care and treatment of all drug-resistant TB patients.
The finding that low BMI was particularly harmful for individuals not living with HIV was unexpected.Rather, we hypothesised that low BMI could be more harmful in the context of HIV due to impaired immune functioning.While this unanticipated finding may be due to chance, an alternative explanation is that low BMI reflects social and medical histories that may vary by HIV status.For example, low BMI may be more likely to represent advanced TB disease among individuals without HIV than those living with HIV.A low BMI resulting from advanced HIV may be less likely than a low BMI resulting from advanced TB disease to impact TB-related outcomes.A second example is that patients with HIV may be more likely than those without HIV to have low BMI due to food insufficiency (and, therefore, may be more likely to respond to monthly nutritional support packages provided during TB treatment) [34].The major limitation of this analysis was an inability to discern between different contributors to low BMI.Future analyses could incorporate markers of food insecurity, recent weight loss, and/or qualitative in-depth interviews to elucidate the prevailing causes of low BMI and identify promising interventions.
Among the other limitations of this analysis is the lack of information on baseline HIV control and its correlates (i.e.adherence to antiretroviral therapy, time on antiretroviral therapy) which may influence BMI and TB treatment outcome.Additionally, while we hypothesise that treatment delays may have contributed to the high prevalence of low BMI at baseline, we did not have data on the onset of symptoms to confirm this hypothesis.
In conclusion, low BMI was common among patients treated with MDR/RR-TB and appeared to impact the frequency of six-month culture conversion and favourable EOT outcomes.Addressing the multiple factors that drive low BMI in this setting will require a multipronged approach focused on alleviating food insecurity and enabling prompt diagnosis and treatment of HIV and TB to hasten culture conversion and improve end-of-treatment outcomes.

Table 2 .
Multivariable analyses of low BMI and culture conversion and favourable treatment outcome among patients initiating treatment for rifampicin-or multidrug-resistant tuberculosis in Lesotho, 2015-2018.Confidence interval.EOT: End-of-treatment.†Adjusted for age, marital status, anaemia, HIV infection, resistance profile at baseline, and numbers of likely effective Group A drugs.‡Adjusted for age, HIV infection, diabetes, at least one other comorbidity, bilateral disease, cavitary disease, fibrosis, positive sputum culture at baseline, resistance profile at baseline, and numbers of likely effective Group A drugs.
Figure 1.Forest plot of the adjusted relative risk of low BMI on culture conversion within six months or favourable EOT outcomes, stratified by HIV status.RR: Relative risk.CI: Confidence interval.EOT: End-of-treatment.

Table A4 .
Univariate logistic regressions of baseline variables and favourable EOT outcome among patients initiating treatment for rifampicin-or multidrug-resistant tuberculosis in Lesotho, 2015-2018 (N = 250).